Controlled release solid preparations are useful in medical use since the number of administration can be reduced and administrative manner can be improved by controlling the concentration of active ingredient in blood; prolonged action of active ingredient short in period of dissipation half decay in living organisms can be improved; and side-effect of active ingredient narrow in width between minimum concentration in blood and side-effect developing concentration in blood can be reduced.
For controlling dissolution of active ingredient to slow release, a method of uniformly dispersing active ingredient together with a dissolution-controlling base substance and compression molding the dispersion is practically used because stable dissolution control can be attained, and structure and production process are simple and rapid development can be made (matrix system). As the dissolution controlling base substances, there are used hydrophilic dissolution-controlling base substances, lipophilic dissolution-controlling base substances, inert dissolution-controlling base substances (belonging to thermoplastic polymers), etc.
As examples of hydrophilic dissolution-controlling base substances, there are known cellulose derivatives such as methyl cellulose (MC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), etc. as disclosed in Patent Document 1, etc. These base substances have characteristics that they can control the active ingredient to slow release without being affected with pH and are superior in time stability. However, cellulose derivatives are greatly swollen by hydration, and hence the solid preparation is greatly swollen in compression direction in a dissolution solution with progress of gelation. As a result, diffusion distance for dissolution of active ingredient becomes longer in the later period of dissolution, causing decrease of dissolution speed. Therefore, they have a defect that it is difficult to accurately control to zero-order dissolution. Commercially available cellulose derivatives include generally those grades which are different in viscosity, and those of high viscosity are superior in ability to slowly release the active ingredient. However, those of higher viscosity tend to be greater in swelling in compression direction, and can hardly accurately control to zero-order dissolution.
Patent Documents 2, 3, etc. disclose a method of adding water-soluble ingredients as a method for adjusting dissolution properties of cellulose derivatives. Patent Document 2 discloses to use sorbitol and polyethylene glycol as dissolution-adjusting agents for slower or faster release in controlled release solid preparations containing a gel-forming polymer such as HPMC as a dissolution-controlling base substance. However, Patent Document 2 has no examples of using the dissolution-adjusting agents and does not specifically disclose effects obtained by using the dissolution-adjusting agents. Furthermore, as known for one skilled in the art, these dissolution-adjusting agents are expected to exhibit the effect to totally delay or hasten the dissolution speed of active ingredient, but cannot improve the problem of decrease in dissolution speed in the later period of dissolution. Patent Document 3 mentions controlled release solid preparations using a cellulose polymer compound such as HPMC as a dissolution-controlling base substance and containing glucose syrup, and discloses that the active ingredient is linearly dissolved. However, in the results of a dissolution test given in Examples, the dissolution rate decreases in the later period of dissolution, and thus decrease of dissolution speed in the later period cannot be improved sufficiently.
Patent Document 4 discloses a method of using a multilayer tablet comprising a swelling layer containing active ingredient and an erosive and/or soluble layer for the purpose of improving the decrease of dissolution speed in the later period of dissolution caused by swelling of cellulose derivative. According to this method, the erosive and/or soluble layer diminish in the later period of dissolution, to cause increase of the surface area of the swelling layer containing active ingredient and thus to inhibit decrease of dissolution rate in the later period of dissolution. However, in order to improve the problem of decrease in dissolution speed in the later period of dissolution, complicated design for preparation is required.
Moreover, in a solution having great ionic strength value, cellulose derivatives compete for hydration with solute which gives ionic strength. Thus, gelation is insufficient and the form of matrix cannot be maintained and broken. It is known that the ionic strength value in gastrointestinal tracts differs depending on not only the areas, but also on the foods taken, and it changes in the range of about 0.01 to about 0.2. Therefore, cellulose derivatives further have the problem that they are inhibited from hydration at an ionic strength of medium or higher value in an environment of gastrointestinal tracts where ionic strength changes, resulting in breakage of matrix. If so-called dose dumping occurs where abrupt dissolution of the remaining active ingredient occurs due to breakage of matrix, concentration in blood abruptly rises. As a result, death may be caused according to the efficacy of the active ingredient narrow in width between the minimum concentration in blood and the side-effect developing concentration in blood. It is necessary that controlled release solid preparations in the field of medicines perform are accurately controlled in dissolution of active ingredient also in the environment of gastrointestinal tracts where ionic strength changes. Therefore, there are demanded controlled release solid preparations having stable dissolution controllability in a solution where ionic strength changes, particularly, in a solution of high ionic strength.
Patent Documents 5-9 relate to methods for improving the dissolution controllability of HPC and HPMC. These documents disclose methods for finely dividing HPC and HPMC to contain 50% by weight or more of particles passing through a 100 mesh (about 150 μm-mesh) sieve for HPC and 95% by weight or more of particles passing through a 100 mesh (about 150 μm-mesh) sieve for HPMC. According to these methods, hydration rate is accelerated by finely dividing HPC and HPMC, a gel layer can be rapidly formed, and disintegration of tablets which occurs in the initial period of dissolution of active ingredient can be inhibited to prevent excessive dissolution. However, use of the fine particles in Patent Documents 5-9 does not improve swelling of particles. Therefore, it cannot improve the problem of decrease in dissolution speed in the later period of dissolution, and besides cannot solve the problem of disintegration in a solution of high ionic strength.
Among cellulose derivatives, HPMC is one of the dissolution-controlling base substances which have hitherto been used most frequently. However, in addition to the above problems, HPMC has further problems in physical properties of powder that it is inferior in flowability, has somewhat yellowish color and is inferior in whiteness and has irritating odor peculiar to synthetic paste, and these many problems are desired to be solved.
As other hydrophilic dissolution controlling base substances of cellulose derivatives, there are known non-cellulose polysaccharides such as xanthan gum and locust bean gum, and synthetic polymers such as polyethylene oxide and acrylic polymers. These dissolution-controlling base substances have such properties that generally they are greater in swelling than cellulose derivatives and greatly swell not only in the compression direction, but also in the direction perpendicular to the compression direction, and are enlarged with lapse of time. Therefore, they have a defect that dissolution speed decreases in the later period of dissolution. In addition, since there is the possibility of causing change in residence time in gastrointestinal tracts, they are not necessarily satisfactory controlled release solid preparations in the field of medicines in which good reproducibility and accurate dissolution are required.
Patent Documents 10-12 disclose methods of adjusting dissolution by adding water-soluble ingredients to non-cellulose polysaccharides or synthetic polymers. Patent Document 10 discloses controlled release solid preparations which contain a heteropolysaccharide gum or a homopolysaccharide gum crosslinkable with the heteropolysaccharide gum and further contain a monosaccharide, disaccharide or polyhydric alcohol as an inert diluent. However, it makes no mention of influence given by the inert diluent on dissolution of active ingredients.
Patent Document 11 discloses controlled release solid preparations containing a carrier for release control such as sodium alginate or xanthan gum and a gel hydration accelerator. It discloses that a mixture of HPMC and propylene glycol alginate ester is preferred as the gel hydration accelerator. It further discloses that since non-gelling core is not formed due to the rapid gel hydration, the dissolution is not influenced by movement speed of gastrointestinal tracts, and zero-order dissolution may occur. However, the controlled release preparations disclosed in Examples are all those in which dissolution of active ingredient hardly occur for two hours after starting of test, and are special ones differing in dissolution from zero-order dissolution generally required in the use of medicines.
Patent Document 12 discloses controlled release solid preparations containing a polymer which forms hydrogel, such as polyethylene oxide (PEO), and at least one additive which has such a solubility that amount of water necessary for dissolving 1 g of the additive is 5 ml or less and which is for causing penetration of water into the preparations. It discloses that since gelation of solid preparations is accelerated, controlled release of the active ingredient becomes possible continuously even in lower alimentary canals in which less water is present. However, it makes no mention of influence given by the difference in molecular weight on strength or dissolution of controlled release solid preparations after gelation. Furthermore, in the dissolution test results disclosed in Examples, dissolution speed decreases in the later period of dissolution, and the problem of decrease in dissolution speed of polymer forming a hydrogel in the later period of dissolution has not yet been solved.
As lipophilic dissolution-controlling base substances, there have been used glycerides such as hydrogenated castor oil, stearic acid glyceride and palmitic acid gryceride, higher alcohols such as cetyl alcohol, fatty acids such as stearic acid, and fatty acid esters such as propylene glycol monostearate. However, these dissolution-controlling base substances have many problems that they lack storage stability, dissolution of active ingredient greatly changes, and dissolution speed of active ingredient decreases in the later period of dissolution.
As the inert dissolution-controlling base substances, there are known polyvinyl chloride, polyethylene, vinyl acetate/vinyl chloride copolymers, polymethyl methacrylate, polyamides, silicone, ethyl cellulose, polystyrene, etc. However, controlled release solid preparations using inert dissolution-controlling base substances develop controlled release due to diffusion of active ingredient through pores formed by compression molding of water-insoluble particles, and hence there is a problem that dissolution speed of active ingredient also changes when size of the pores changes by compression molding pressure. There is another problem that diffusion distance of active ingredient increases in the latter half period of dissolution to result in decrease of dissolution speed.
Patent Documents 13, 14, etc. disclose methods for adjustment of dissolution by adding a water-soluble ingredient to the inert dissolution controlling base substance. Patent Document 13, etc. disclose controlled release solid preparations containing a methacrylic acid copolymer as a dissolution-controlling base substance and an excipient such as D-sorbitol, powdery reduced maltose syrup or anhydrous calcium phosphate. It discloses that by using the solid preparations, dissolution of active ingredient is proportioned to time and does not depend on compressive force. However, in the dissolution test results disclosed in Examples, dissolution speed decreases in the later period of dissolution, and the problem of decrease in dissolution speed of methacrylic acid copolymer in the later period of dissolution has not been solved. Moreover, change in dissolution speed caused by compression molding pressure is not inhibited. The methacrylic acid copolymer commercially available as medicine additives is apt to generate static electricity and besides has a peculiar strong offensive odor, causing problem in handling.
Patent Document 14 discloses a method for increasing or decreasing the releasing rate by adding water-soluble, water-soluble and highly swelling or lipophilic excipient such as polyethylene glycol for changing release to controlled release solid preparations containing a mixture of polyvinyl acetate and polyvinyl pyrrolidone as a dissolution-controlling base substance. This method totally controls dissolution of active ingredient by controlling water permeability through pores formed by compression molding of polyvinyl chloride. However, the problem of decrease in dissolution speed in the later period of dissolution has not been solved. It further discloses that gel is formed on the surface of tablet to inhibit initial dissolution, and hence the dissolution occurs linearly. However, the problem of decrease in dissolution speed in the later period of dissolution cannot be solved, and does not specifically mention use of polyethylene glycol or linear dissolution in Examples. Furthermore, the mixture of polyvinyl acetate and polyvinyl pyrrolidone commercially available as an additive to medicines has strongly yellowish color and strong offensive odor peculiar to chemical synthetic products.
Patent Document 15 discloses a modified starch of 400% or more in water retaining capacity, 5 hours or more in disintegration time and 200 g or more in gel indentation load, and controlled release solid preparations having the modified starch as a dissolution-controlling base substance. It discloses that the above modified starch has a high resistance to α-amylase which is not seen in conventional natural modified starch, and hence shows sufficient controlled release and is not affected by ionic strength, and, therefore, there is no problem of dose dumping and controlled release of active ingredient can be relatively stably performed. In addition, it is produced only by physical processing of starch material in nature. Therefore, the starch has no problem of remaining chemical substances and can be taken without anxiety, and besides is satisfactory in both the flowability and whiteness. However, the modified starch disclosed is relatively high in swelling of particles, and has defects that strength of gelling solid preparation is low, and dissolution speed of active ingredient changes by the compression molding pressure. Moreover, the dissolution of active ingredient greatly changes with changing of compression molding pressure in production process or changing of formulation and amount. Therefore, the dissolution cannot necessarily be accurately controlled. Moreover, if an active ingredient low in solubility in water is used, cracking or breaking in two occurs in solid preparation during unspecified period in the course of dissolution, particularly, under the condition of small compressive force in compression molding, and as a result, dissolution speed is temporarily increased. Further, in the case of a formulation in which content of active ingredient is high, the content of modified starch is restricted to small level. Therefore, the gel layer formed on the solid preparation is relatively low in strength, and tablets are cracked or broken due to the swelling force of solid preparation per se caused by swelling of the modified starch. As a result, there is the problem that a large amount of active ingredient is abruptly released. Thus, the modified starch disclosed in Patent Document 15 can accurately control the dissolution independently of the environments in living organisms such as ionic strength and pH, while it has the problems that dissolution speed changes depending on compression molding pressure, and a large amount of the active ingredient is abruptly dissolved and released in unspecified period depending on the kind and content of the active ingredient.
Use of starches as dissolution-controlling base substance is disclosed in Patent Documents 16-22, etc. Patent Document 16 discloses a pharmaceutical composition containing pregelatinized starch having low viscosity and a particle size of multimode for the purpose of improving variation of dissolution speed of active ingredient. It is disclosed that this composition can be used in many modes including continuous release. However, Examples disclose only such preparations as high in dissolution speed of 75% or more in 45 minutes, and make no specific disclosures indicating controlled slow release. Furthermore, Patent Document 16 differs from the present invention mentioned hereinafter because it does not mention that starch per se has controlled releasing function.
Patent Document 17 discloses controlled release preparations having previously gelatinized starch as a matrix base substance. However, as a preferable embodiment, it discloses use of previously gelatinized corn starch having 10-20% of soluble fraction, which is different from the modified starch used in the present invention which contains 40-95% of a water-soluble ingredient. The dissolution speed of active ingredient is not specifically disclosed. However, the starch of Patent Document 17 which is less in content of ingredient soluble in cold water is insufficient in controlled releasing function, and particularly can hardly control active ingredient having high solubility in water to be slowly released.
Patent Document 18 discloses a matrix controlled release preparation containing at least one of water-soluble polymers and polymers lower in water solubility. Patent Document 19 discloses a matrix controlled release preparation containing both the water-soluble polymer and polymer lower in water solubility. Patent Documents 18 and 19 disclose starch as a water-soluble polymer, but this is different from the modified starch used in the present invention which contains water-soluble ingredient in the range of 40-95% and dissolves only partially in water.
Patent Document 21 discloses a controlled release preparation using as a matrix base substance a starch obtained by applying shear to a mixture of water and 5-95% of starch at a temperature of 130 to 160° C. Patent Document 22 discloses a controlled release preparation using a starch obtained by removing crystallinity of crystalline starch partially or substantially completely. However, in Patent Documents 21 and 22, dissolution of active ingredient cannot be controlled to zero-order dissolution and the like.
Patent Documents 23-25 disclose controlled release preparations using amylose as a matrix base substance, but which are different from the modified starch used in the present invention in that this contains amylose and amylopectin. Patent Documents 26-28 disclose controlled release solid preparations using crosslinked amylose as a matrix base substance. However, the crosslinked amylose is obtained through troublesome steps, namely, by removing amylopectin from natural starch to obtain an amylose and subjecting the amylose to a chemical treatment in the presence of an alkali. Furthermore, when crosslinked amylose is used, it is necessary to add α-amylase as a dissolution speed adjustor to improve dissolution controllability (Patent Document 27) or to use HPMC for lowering dependence on α-amylase present in intestinal environment (Patent Document 28).
Patent Document 29 discloses controlled release preparations using starch acetate as a matrix base substance, Patent Document 30 discloses controlled release preparations using substituted amylase, which is substituted with epoxy group or halogen compound, as a matrix base substance, and Patent Document 31 discloses controlled release preparations using starch modified with carboxylic acid or sulfate as a matrix base substance. Patent Documents 29-31 require chemical treatment in order to impart controlled release function to starch and are different from the present invention in that the modified starch used in the present invention is obtained only by subjecting natural starch to physical treatment.
As mentioned above, in the conventional technologies, there are no controlled release solid preparations which are not affected by environments in living organisms such as ionic strength and pH, compressive force in compression molding, and kind and content of active ingredient, less in change of residence time in gastrointestinal tracts, and can be controlled in dissolution of active ingredient to zero-order dissolution, two or more stage dissolution or timed-dissolution, and such controlled release solid preparations have been desired.    Patent Document 1: U.S. Pat. No. 6,296,873    Patent Document 2: JP-A-2005-504052 (US2004197404)    Patent Document 3: JP-A-2002-525310 (U.S. Pat. No. 6,733,782)    Patent Document 4: JP-A-2004-107351 (U.S. Pat. No. 5,549,913)    Patent Document 5: JP-B-51516    Patent Document 6: JP-B-7-8809    Patent Document 7: JP-A-62-149632    Patent Document 8: JP-A-6-172161    Patent Document 9: JP-A-6-305982 Patent Document 10: JP-A-2003-510265 (EP1135106)    Patent Document 11: JP-A-2004-143175 (US2004081693)    Patent Document 12: JP-A-2001-10951    Patent Document 13: JP-A-11-5739    Patent Document 14: JP-A-2002-20319 (US2002012701)    Patent Document 15: WO2005/005484A    Patent Document 16: JP-A-2006-514687 (EP1536788)    Patent Document 17: JP-A-5-262649    Patent Document 18: JP-A-63-54319    Patent Document 19: JP-A-2-209    Patent Document 20: JP-A-63-503225    Patent Document 21: WO92/15285    Patent Document 22: JP-A-61-5027    Patent Document 23: JP-A-2000-517351 (US2002192291)    Patent Document 24: WO99/009066    Patent Document 25: JP-A-2002-363106    Patent Document 26: U.S. Pat. No. 5,456,921 (U.S. Pat. No. 5,456,921)    Patent Document 27: JP-A-8-502036 (EP0651634)    Patent Document 28: JP-A-2000-507561 (U.S. Pat. No. 5,885,615)    Patent Document 29: JP-A-10-502056 (U.S. Pat. No. 5,667,803)    Patent Document 30: JP-A-2001-502700 (U.S. Pat. No. 5,879,707)    Patent Document 31: WO2005/74976A    Non-Patent Document: Chem. Pharm. Bull. 35(10), 4346-4350 (1987)